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Basic Pathology
Fifth edition

Basic Pathology
An introduction to the mechanisms of disease

Sunil R Lakhani BSc MBBS MD FRCPath FRCPA

Professor and Head, Molecular and Cellular Pathology, School of Medicine,
University of Queensland and State Director, Anatomical Pathology,
Pathology Queensland, Brisbane, Australia

Susan A Dilly BSc MBBS FRCPath

Emeritus Professor of Pathological Sciences, Barts and The London Medical
School, Queen Mary University of London, UK

Caroline J Finlayson MBBS FRCPath

Formerly Honorary Senior Lecturer and Consultant in Histopathology,
St George’s Hospital Medical School,
London, UK

Mitesh Gandhi MBBS MRCP FRCR FRANZCR

Princess Alexandra Hospital and Queensland X-ray, Woolloongabba,
Brisbane, Australia
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742

© 2016 by Sunil R. Lakhani, Caroline Finlayson, Susan A. Dilly, and Mitesh Gandhi
CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Printed on acid-free paper

Version Date: 20160201

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 CONTENTS

Preface
Acknowledgements
PART 1 Disease, health and medicine 1
Introduction: Disease, health and medicine 3
Chapter 1: What causes disease? 7
Chapter 2: What are the common mechanisms of disease? 40
PART 2 Defence against disease 87
Introduction: The role of epidemiology in disease 89
Chapter 3: The body’s response to infection 95
Chapter 4: The acute inflammatory response 109
Chapter 5: Healing and repair, chronic and granulomatous
inflammation 147
Chapter 6: Chronic inflammation and the adaptive
immune response 178
Part 3 Features of cardiovascular disorders 209
Introduction: Features of cardiovascular disorders 211
Chapter 7: Vascular occlusion and thrombosis 215
Chapter 8: Atherosclerosis and hypertension 235
Chapter 9: Circulatory failure 258
Part 4 Cell growth and its disorders 291
Introduction: A brief history of cancer 293
Chapter 10: Benign growth disorders 295
Chapter 11: Malignant neoplasms 305
Chapter 12: What causes cancer? 320
Chapter 13: Molecular genetics of cancer 332
Chapter 14: The behaviour of tumours 354
Chapter 15: The clinical effects of tumours 361
Epilogue 373
Index 374
 PREFACE
‘What is the use of a book’, thought Alice, ‘without
pictures or conversations.’
Lewis Carroll
Any artist will tell you that in drawing objects, you
cannot ignore the spaces in between: the picture ceases
to exist when only one aspect is viewed in isolation.
Musical pieces composed entirely of notes and without
pauses would be nothing more than a noise and an irri-
tation. Yet when it comes to teaching, we may ignore
this fact and fail to put our own specialty into the con-
text of the whole curriculum.
Over the last decade, there has been a trend towards
a more integrated approach to medical education. We
are delighted that such an approach, which we have
always used in our teaching, is now widely adopted
throughout the world.
Our aim in this book has been to create a tutorial
on the mechanisms of disease over a background of
history, science and clinical relevance. The goal is to
give the student a sense of belonging to a movement,
the movement from past to present and from cell to
patient.
This book has been written in the hope that the stu-
dent will read the text fully and at leisure. This not only
contains detail about the disease processes but also his-
torical anecdotes and clinical scenarios. The cartoons
are intended to amuse as well as illustrate the import-
ance of certain topics, and we sincerely hope that stu-
dents reading the book will be able to shed the dull,
dreary image of pathology that they all seem to be born
with. Pathology is one of the most fascinating and fun
subjects students are likely to encounter during their
undergraduate training. If you understand the basic
principles of disease, then the interpretation of clinical
symptoms and signs, the rationale behind investigation
and treatment, and the unravelling of complex cases
become more logical. Time spent building a framework
of mechanisms will assist your clinical practice.
This fifth edition of Basic Pathology can be used in
conjunction with a companion volume called Pathology
in Clinical Practice: 50 Case Studies, which is designed to
help you use your pathology knowledge in clinical set-
tings. Some extracts from Pathology in Clinical Practice
are included in this book as well as links to the full cases
highlighted with a ‘link’ symbol.
Read more about bacterial infection in
Pathology in Clinical Practice Case 7
When you access the e-book of Basic Pathology, either
via the unique code printed in your hard copy or if you
have purchased the e-book only, you will have access
to the full text of both titles, and hyperlinks from Basic
Pathology will take you directly to relevant cases in
Pathology in Clinical Practice. We hope that you will find
these stimulating, fun and complementary to this book
because they contain more advanced, clinically relevant
information.
This edition introduces radiological images in place
of some of the traditional autopsy-based photographs
of diseased organs. We recognise how significantly
technology has changed everyday clinical practice and
students are expected to be familiar with the increasing
repertoire of scanned images. Over the next decades,
the same may become true for genomic information,
and we have extensively revised and expanded these
sections.
This book is primarily intended for medical students,
but should also be useful to students of dentistry, human
biology and other health professions. Postgraduate stu-
dents studying for pathology or surgical exams may also
wish to consult these books.
 ACKNOWLEDGEMENTS
When we set out more than 20 years ago to write a
textbook in which we would take the students on a
journey, from past to present and from patient to the
cell and back again, the phrase ‘integrated curricu-
lum’ was not in common usage. Today, most medical
schools have switched to the new-style curriculum in
which pathology is taught as an integrated subject with
other disciplines. With each version of this book, there
has been a move towards greater integration, especially
with our colleagues in radiology who share our key role
in diagnosing and monitoring disease in patients. We
have also been influenced considerably by the many
clinicians who attend joint clinico–pathological meetings
to discuss individual patients and the best approach for
their clinical management. All these should be acknow-
ledged as informing and shaping this book.
In addition, our endeavours to produce this fifth edi-
tion have been considerably aided by help, comments
and constructive criticism from a number of people,
and we would like to acknowledge their time and
effort. In particular, thanks to Peter Riley, Alison Milne
and Alex Roche for their useful comments. This book
has evolved through each edition and all contributors
to earlier editions have influenced this latest version.
They include Professor Philip Butcher, Professor Mike
Davies and Dr Grant Robinson at St George’s Hospital;
Dr Ahmet Dogan, one of our co-authors from the third
edition, and Dr Barry Newell, the lead author on the
companion volume of Pathology in Clinical Practice.
Dr Peter Simpson and Dr Amy McCart Reed from
Brisbane made a useful contribution to the molecular
sections of the current edition.
We would like to thank the staff of Queensland X-ray
and the radiology department of the Princess Alexandra
Hospital, Brisbane for their help in providing the
radiology images which have been used.
Finally, and most importantly, we would like to
thank our families for their encouragement and sup-
port. But for their understanding, it would be difficult
to get away with the disproportionate amount of time
that such projects consume.
SRL, SAD, CJF, MG
2016
PArT 1
DISEASE, HEALTH AND
MEDICINE

Introduction: Disease, health and medicine 3

Chapter 1: What causes disease? 7

Chapter 2: What are the common mechanisms of disease? 40

1
 INTroDuCTIoN
DISEASE, HEALTH AND
MEDICINE
Medicine, to produce health, has to examine disease.
Plutarch (c. 46–120)
Greek biographer and essayist
Medicine is the science and practice of diagnosing,
treating and preventing diseases and it depends on
understanding the mechanisms of disease – the topic
of this book.
Diseases have causes (aetiology) and mechanisms
(pathogenesis). They may produce symptoms (experi-
enced by the patient) and signs (elicited by the phys-
ician). There may be structural changes that are visible
to the naked eye (gross or macroscopical appearances),
or only detectable down a microscope (microscopical
appearances). Functional changes may be apparent to
the patient or only detected by clinical or laboratory
tests. All of this is pathology, and pathology is the study
(logos) of suffering (pathos).
Our approach to investigating mechanisms has, how-
ever, changed significantly over the last 25 years from
a simple linear cause-and-effect approach (reduction-
ism) to an appreciation of the significance of complex
interactions (holistic approach). Huge advances in com-
puter technology have allowed modelling of complex
systems that would not previously have been possible
and this is opening up whole fields of new research (the
‘omics’). The problem for a doctor or student is that
this is mind-boggling and, in day-to-day life, we rely on
simpler concepts that have practical application to the
patient in front of us, so we acknowledge the complex-
ity but adopt the simplistic.
Generally in this book we use a mechanistic model
that regards the body as a machine with repairable or
replaceable parts. It places a high emphasis on the scien-
tific evidence base for untangling cause and effect in both
the disease and its treatment, because this is important
for patient care and prognosis. We also describe ‘asso-
ciations’ that have been identified between various
factors and diseases but where no clear mechanism has
been discovered to explain the link. These are areas of
intense research and worth reading about in research
journals to learn the latest ideas.
So how would you define ‘disease’? In fact, this is
fraught with problems because disease definitions
change with time and across cultures. Do you, in fact,
need to suffer from a disease as part of the definition?
Does a person have the disease before the symptoms
appear? This is particularly important now that there
is screening for many diseases and people may have
abnormal ‘disease markers’ without any symptoms, or
the ‘disease marker’ occurs in people who will never
have the disease. This can lead to over-treating people
who have lesions considered as premalignant but who
would never develop invasive cancer, or people who
have raised blood pressure but might not have a stroke
or heart attack.
With those caveats, we offer a biomedical defin-
ition of disease – ‘Disease occurs when homeostasis
fails’. Homeostasis is the concept of a regulated system
that maintains equilibrium (a balanced state) within
Introduction: Disease, health and medicine
the body, despite changes in the internal or external
environment. If you accept this definition then under-
standing the mechanisms of disease will involve under-
standing the processes for maintaining homeostasis,
identifying the agents and events that disrupt homeosta-
sis, trying to determine why homeostatic mechanisms
fail, and testing treatments that can alter the sequence
of events and restore health. A disease should have the
potential to produce some impairment of function, but
may be detected while asymptomatic. It may also be
treated or heal through the body’s normal processes so
that no permanent damage is produced.
Let us take the example of lobar pneumonia (see
Chapter 4, fig 4.25) and the key concept of homeosta-
sis and introduce a diagram that helps to illustrate the
various components of the disease process (Fig. 1).
3
 4 Introduction: Disease, health and medicine

Disease
agent

Cell
Tissue Resolution
Organ Bacteria
Person
Adaptive response
Structural changes involving internal Treatment
Functional changes factors

Symptoms
Signs
(a)

Acute inflammatory response

Consolidation (structural change)
Reduced gas transfer in alveoli
Resolution
(functional change)

Symptoms:
Cough, breathlessness,
Improved gas
haemoptysis
transfer with
Signs:
new equilibrium
Reduced chest movements,
achieved
dull to percussion,
X-ray changes

Oxygen
therapy
Part 1: Disease, health and medicine

Inflammatory
cells produce
Reduced gas
Response =
transfer in alveoli
tachycardia
(functional change)

Pyrogens Hypoxia
(internal factors) (internal factor)

(b)

Figure 1 Disease occurs when homeostasis fails: (a) homeostatic mechanisms restore equilibrium; (b) some
homeostatic mechanisms in lobar pneumonia (green dotted arrow = homeostatic mechanism).
 Introduction: Disease, health and medicine 5

Risk factor
Predisposition
A risk factor confers an
Patients have an increased susceptibility to
increased risk of developing
develop a disease - usually inherited e.g.
a disease, e.g. smoking and
Familial Adenomatous Polyposis patients have a
lung cancer.
mutated APC gene and risk developing colorectal
carcinoma if a succession of mutations occurs in
one or more of their polyps.
Pathogenesis
The pathological mechanism which
results in clinically evident disease, Premalignant
e.g. the way in which the interaction Premalignant is a term for a
between M. tuberculosis and the pathological lesion or process which
host immune system produces the will probably, if untreated,
caseating granulomatous lesion of TB. transform to invasive malignancy,
e.g. high-grade dysplasia in the
cervix. (The aetiological agent is
Human Papilloma Virus.)
Aetiology
The aetiology is the cause of
a disease, e.g. Mycobacterium Disease mechanism
tuberculosis casuses This is the way in which disease-causing agents
tuberculosis (TB). disturb homeostatic mechanisms. Understanding how a
disease evolves can help in prevention or treatment
(e.g. vaccination against HPV virus to prevent cervical
carcinoma).
Disease
Disease is a consequence of failure of
homeostasis. It should have the
potential to produce impairment of function,
even though it may be diagnosed while still
symptomatic (e.g. breast cancer discover
in a screening mammogram).

Introduction: Disease, health and medicine

Figure 2 Don’t be confused by terminology!

In its simplest form, an intrinsic or external factor
(the cause) acts on a cell, tissue, organ or whole per-
son to produce structural or functional changes and a
response. If an adaptive response is 100% successful,
then homeostasis is maintained and no symptoms or
signs result. If unsuccessful, then the disease manifests
and the structural and functional changes may have
an impact on another cell, tissue or organ to produce
another set of reactions. Thus, in lobar pneumonia, the
extrinsic cause is the bacterium, Streptococcus pneumoniae,
which affects the lung. This stimulates an acute inflam-
matory response that can produce the structural chan-
ges of consolidation and functional changes of reduced
gas transfer in alveoli.
The patient has symptoms of a cough, breathless-
ness and, even, haemoptysis (coughing up blood).
The physician may detect the signs of reduced chest
movements, an area that is dull to percussion and radio-
logical opacity reflecting lung solidification. However,
this is not the end of the story.
We can produce another ‘disease sequence’ where
the reduced gas transfer results in hypoxia (reduced
oxygen saturation in the blood), which acts as an
internal factor that leads to the heart responding with
an increased heart rate (tachycardia). More blood
is pumped through the part of the lung, which is not
consolidated, so increasing gas transfer, and this may
successfully compensate so that the hypoxia is cor-
rected, i.e. a new equilibrium is achieved. But before
you relax, look at page 139 where we explain about
pyrogens that may accompany the inflammatory
response to bacteria and the effect that they may have
 6 Introduction: Disease, health and medicine
on the heart. Yes, that is another route for producing
a tachycardia and so our diagram could become almost
infinitely complex as we add the different pathways.
By now, you will have realised why we started by
comparing reductionist and holistic approaches for
understanding mechanisms. In the simplest situation,
we just identify the primary mechanism, treat the
patient with antibiotics against S. pneumoniae, remove
the primary cause and return the patient to health. If
the patient is very unwell and the secondary mechan-
isms are operating, we may need to provide oxygen by
facemask to reduce the hypoxia, i.e. treat the second-
ary factor. We could consider using drugs such as para-
cetamol that have an antipyretic action and will help
counteract the effect of the pyrogens; and so it goes on!
Where should we stop? Are we able to analyse intelli-
gently all the processes that may be operating?
The answer is no but we are making huge leaps for-
ward. We mentioned the ‘omics’, which is the term
used for studying the totality of activities. Genomics is
about analysing the functions and structure of the gen-
ome (i.e. the interactions of all the genes). Proteomics
studies the interactions of all the proteins in a cell,
lipidomics all the lipid-based actions.
If you start off healthy and successfully maintain
homeostasis, surely you should remain healthy. But
Part 1: Disease, health and medicine
do you start off healthy? That leads us to the concept of
predisposition. We each have around 25 000 genes
present in every cell but expressed differently,
depending on the cell type and its response to its
environment. The likelihood of our suffering from
a disease depends on interactions between our genes
and the environment, so called G×E interactions.
The environment, however, starts working from the
moment of conception so even genetically identical
twins may have different predispositions for dis-
eases by the time they are born. This continues on
through life, with our personal ‘exposome’ being
the life-long impact of the various environmental
exposures on our genome and our health. However,
things are rarely inevitable and so you may be able
to identify your higher predisposition for disease,
understand the risk factors that will make mat-
ters worse, avoid those risk factors and so not get
the disease! Preventive medicine in the future may
be much more tailored to individual circumstances
and susceptibility than was previously possible. Drug
treatments may be used only where they will be truly
beneficial. This could be the beginning of an era of
personalised medicine based on individual genome
analysis so understanding the mechanisms of disease
is fundamental – read on!
 CHAPTEr 1
WHAT CAuSES DISEASE?

Physical causes 8 Biological agents as causes of

Clinical scenario: frostbite 8 diseases 16
Chemical causes 10 Inflammatory conditions 22
Case study: coughing up blood 13 Case study: coeliac disease 24
Structural causes 15 Nutritional diseases 26
Which are the most important Genetic causes of disease 27
diseases today? 16 Case study: an abnormal baby 38

Those who are enamoured of practice without science Table 1.1 Categorising the causes of disease
are like a pilot who goes into a ship without rudder
or compass and never has any certainty where he is Category Example of causes and diseases
going. Practice should always be based upon a sound
Physical Heat, cold, radiation, electrical,
knowledge of theory.
mechanical
Leonardo da Vinci (1452–1519)
Italian artist, sculptor, architect and engineer Chemical Tobacco smoke, alcohol, drugs,
poisons, air pollution
Every day we eat food, breathe air, walk, talk and Structural Congenital neural tube defects,
perform the tasks of daily life before going to bed vascular occlusion, bowel
unscathed. Some days, however, we may encounter perforation
and be harmed by viruses, bacteria, unusual antigens, Infectious Bacteria, viruses, fungi, protozoa,
extremes of temperature, chemical pollutants or prions
fast-moving vehicles. We are harmed by environmental
Inflammatory Peanut anaphylaxis, dust-mite
(or extrinsic) factors. The cause is usually obvious if it
asthma, autoimmune conditions

Chapter 1: What causes disease?

happens immediately but may be hard to discern when
the effect takes days or years to manifest, e.g. tobacco
smoking causing lung cancer. In some situations, the
environment plays no part and the cause is entirely gen-
etic (intrinsic), e.g. the anaemias related to abnormal
haemoglobin (see page 279).
There is no particular way of classifying the causes of
diseases but it is useful to have a checklist that you find
helpful when talking with patients and thinking about
their ‘differential diagnosis’, i.e. the possible condi-
tions and the causes that would explain their current
symptoms. Table 1.1 shows such a list of causes, which
are presented in an order that moves from the rela-
tively simple to the more complex, so that you could
Nutritional obesity, malnutrition, diabetes
Degenerative osteoarthritis, dementia
Genetic
identify and treat the straightforward cases quickly.
Depending on your location and specialty, you could
use this approach to construct a flowchart of the most
likely causes for your patients.
We have put genetic causes at the bottom of the list
because the genes interact with most of the other causes
in complex ways. It is possible to produce a GxE (genes
x environment) card to illustrate this, as shown on

7
 8 What causes disease?
page 215. Mostly these causes are based on statistically
derived associations rather than precise knowledge of
the mechanisms but we attempt to highlight the main
mechanisms through which genes affect health.
PHYSICAL CAuSES
Let us start with a physical cause of disease and look
at extremes of temperature.
CLINICAL SCENArIo: FroSTBITE
A 29-year-old skier lost his way after drinking a few
beers in a mountain restaurant. He was discovered,
unconscious, without a hat, 20 hours later in an exposed
location on the mountain face. He had obvious frostbite
to his nose and fingertips, manifest as hard white areas.
A weak, thready, but regular pulse was present and he
was breathing shallowly. He was wrapped in a space
blanket and rushed by helicopter to hospital. His rec-
tal (core) temperature was found to be 30°C. He was
warmed with blankets and hot water bottles. He suf-
fered a cardiac arrest but was immediately resusci-
tated. His mild metabolic acidosis was corrected.
As he regained consciousness he began to shiver vio-
lently and his limbs became reddened and swollen. He
tried to raise himself up but promptly fainted. Over
the next couple of days his fingertips and nose turned
black and the skin began to slough off. At one point it
appeared that he would lose the tips of most of his fin-
gers, but after the skin had fallen off only two fingertips
Part 1: Disease, health and medicine
were lost and his nose was saved (Fig 1.1).
What has happened here?
Our patient was hypothermic, i.e. his core temperature
was <35°C (normal temperature 37°C). He contrib-
uted to his condition by drinking alcohol (see below).
He was not wearing a hat, and 50% of the body’s heat
loss may be through the head. There is no mention of a
facemask, which might have served to warm the freezing
air before he inhaled it, losing core heat when the lungs
warmed the air before exhalation.
The onset of hypothermia is dependent on many
factors, including body build, ambient temperature,
whether the individual is dry or wet, the presence of
Figure 1.1 Frostbite is caused by the freezing
of tissues. Sludging of cells in capillaries causes
ischaemic damage. Endothelial cells are vulnerable
to both cold and hypoxia; on thawing of the tissues,
there is leakage of blood through the damaged
vessels, and the tissue appears blackened over a
larger area than is actually necrotic, so delaying
amputation is advised.
protective clothing and whether or not alcohol has been
ingested (even small amounts can greatly increase the
risk of hypothermia).
Alcohol plus exercise is probably the worst combin-
ation, because not only is his blood glucose depleted by
exercise but also the alcohol interferes with the gener-
ation of new glucose from body stores by reducing the
amount of pyruvate available.
Once he became hypothermic he would have been
less able to make rational decisions or take sensible
measures such as seeking help, finding shelter or cover-
ing exposed areas of his body.
How does the body respond to cold?
Initially the heat gain centre in the hypothalamus dir-
ects the body to shiver violently and shut down periph-
eral blood vessels by vasoconstriction, but if this fails
to restore core temperature the cooling of the heart
interferes with cardiac output. Below 26°C the cardiac
output is too low to sustain life (Fig. 1.2).
Oxygen combines more strongly with haemoglobin
at low temperatures, further depleting tissues of
oxygen. Anoxic effects on the heart include arrhythmias.
Patients whose body temperature is below 30°C are at
risk of cardiac arrest and should be monitored using
ECG. Respiration is diminished, usually in proportion
with tissue requirements, but slight CO2 retention may
 Physical causes 9

Core
Lungs:
• ↓respiration due to ↓oxygen
demand from tissues →
retention of CO2 and
respiratory acidosis, which is CENTRE
superimposed on lactic Shivering
acidosis from shivering
Kidneys:
• Cold diuresis occurs
• Renal tubular epithelium
damaged by cold, fails to
reabsorb sodium → ↓plasma
osmolality, water →tissues
Peripheries:
>12°C
• Numbness: membrane sodium
pump inactivated, nerves and
TEMP muscles inexcitable
• Capillary endothelium damaged
Peripheral by cold <–0.5°C
vasoconstriction • Freezing of tissues damages
endothelial cells
• Sludging of cells in blood vessels
causes hypoxia or infarction. On
thawing, blood and plasma leak
into tissues and ↓blood volume
Core

Vasculature:
• Circulating blood volume
reduced
• Oxygen less readily given up
to tissues by oxyhaemoglobin
at low temperatures

Heart:
• Reduced cardiac output due
to ↓blood volume and ↓myocardial Increased susceptibility to cold if:
contractility • Skin is wet
• Risk of arrhythmias • Elderly or very young
• Risk of cardiac arrest, 30°C • Homeless or exposed to the elements
• Cardiac output cannot sustain life, 26°C • Alcohol consumed (or other
Peripheries vasodilator)
Muscles and nerves: • Concurrent infection (temperature
• Lose excitability due to impaired centre may be compromised)
membrane Na+ pump
• Severe pain on thawing

Figure 1.2 Changes associated with cold and reperfusion.

cause a respiratory acidosis, compounded by the meta- What is frostbite?

bolic acidosis that occurs when lactic acid accumulates Frostbite is the result of the freezing of tissues, which
as a result of shivering. occurs at temperatures below -0.54°C. Before freezing,

Chapter 1: What causes disease?

Why did the patient faint as he began to
recover?
Blood volume falls in the hypothermic patient due
to a combination of a ‘cold diuresis’ which occurs in
response to a drop in core temperature, and damage
to the renal tubular epithelium as a result of the cold,
preventing sodium reabsorption; this causes a drop in
plasma osmolality and water moves out of the vascu-
lar compartment into the tissues to balance this. When
the patient is warmed and vasodilatation occurs the
blood volume is insufficient for demand and there is
hypotension.
cooling to <12°C causes paralysis of muscles and nerves
by interference with the membrane sodium pump.
Lack of sodium ions renders nerves and muscles inexcit-
able. Damage is reversible after a few hours, but not if left
longer. If the tissue freezes, the tissue proteins become
denatured and the cell dies. Vascular endothelial cells are
particularly susceptible. When they thaw, plasma leaks
out of the small vessels through the damaged endothel-
ium and the retained red blood cell sludge, obstructing
the lumen and causing local infarction of tissue.
Although it is dangerous to warm the body of a hypo-
thermic person too quickly, if a patient is suffering only
from frostbite it is best to warm the affected area as
 10 What causes disease?
quickly as possible, so that sludging and infarction are
reduced to a minimum due to quick restoration of
blood flow. It is harmful to thaw an area of frostbite and
then allow it to refreeze, as may happen on a moun-
tainside when colleagues treat the area by warming and
then the patient with frostbite is carried back through
the same harsh environmental conditions which caused
the problem.
Although damage may seem extensive, the actual
area of necrosis may be less than it first appears and it
may be worth waiting for a few days before amputat-
ing an affected area. The process of thawing out is very
painful and requires analgesic support, plus elevation of
the affected area to reduce tissue swelling.
CHEMICAL CAuSES
The most common chemical causes of diseases are in
the air that we breathe, whether we are indoors or
outside. The contaminants in the air vary considerably
Deaths attributable to outdoor air pollution, 2008
Part 1: Disease, health and medicine
Deaths per 100 000
population
0–5
6–10
11–20
21–40
>40
Data not available
Not applicable
Figure 1.3 Deaths attributable to outdoor air pollution. (From WHo global observatory map.
© WHo 2011. All rights reserved.)
depending on the season and the location, but included
among them are substances that cause life-threatening
lung inflammation and cancer. Indoors, the major
hazards are tobacco smoke and wood smoke. Outside
they can be a mixture of pollutants, most of which
come from industrial production, home heating and
car exhaust fumes (Fig. 1.3). In cities, ozone is a par-
ticular problem because it is produced by the action
of sunlight on nitrogen oxides from car exhausts, and
so can be present in large amounts. Ozone generates
free radicals (see section on cell damage) which dam-
age the lining cells of the lung, so decreasing lung
function and increasing airway reactivity and inflam-
mation. Particles are also damaging, especially if they
are carried down to the alveoli rather than being
trapped and cleared by the mucus. In the alveoli,
they can stimulate macrophages and provoke chronic
inflammation. These effects can limit the activities of
healthy people and cause hospitalisation for people
with asthma or chronic lung conditions (Fig. 1.4).
It is increasingly recognised that air pollution also
causes lung cancer, yet environmental controls fail to
 Chemical causes 11

adequately reduce air pollution. In Europe, the limit
is set at 25 mg/m3 but this is higher than the level
causing damage and studies on 360 000 city residents
show a 7% increase in mortality rate for each 5 mg/m3
increase in fine particulates.
Indoors, wood smoke is an irritant that contains
carcinogenic polycyclic hydrocarbons, which cause
recurrent lung infections and bronchial tumours.
The most significant, readily avoidable, chemical air
pollutant is tobacco smoke. Tobacco smoke is a complex
mix of substances, some of which cause immediate dam-
age by irritating airways and stimulating inflammation
and mucus production, resulting in cough and reduced
exercise tolerance. In the medium to long term, the
recurrent inflammation causes chronic obstructive
Outdoor air pollutants
ozone Acid aerosols
Nitrogen dioxide Particulates
Sulphur dioxide
pulmonary disease (COPD) and emphysema, which
are irreversible. The risk of lung cancer depends on the
number of cigarettes smoked in a roughly linear rela-
tionship and the overall survival is reduced by around
7 years for smokers compared with those who have
never smoked. Most of the harmful effects are on the
lungs and cardiovascular system; however, there are
also organ-specific carcinogens in tobacco smoke caus-
ing tumours in the oesophagus (N´-nitrosononicotine or
NNN), pancreas [4-(methylnitrosamino)-1-(3-pyridyl)
-1-butanone or NNK], bladder (4-aminobiphenyl and
2-naphthylamine) (Fig. 1.5) and oral cavity (polycyclic
aromatic hydrocarbons, NNK and NNN). Combining
tobacco smoke with alcohol significantly increases the
risk of laryngeal, oral and oesophageal cancer.
Some of the components of tobacco smoke and their
effects are listed in Table 1.2.
The list in Table 1.2 does not explain the major
effects of tobacco on the cardiovascular system,
which is believed to be the cause of a third of heart
attacks. This is also discussed in the section X CVS
atheroma (page 239) but, briefly, it is likely that
the combination of damage to vascular endothel-
ial cells, hypoxia and increased platelet aggregation

DALYs attributable to household air pollution, 2004

Chapter 1: What causes disease?

DALYs per 100 000
population
<20
20–250
251–500
501–1000
1001–2500 Data not available
>2500 Not applicable

Figure 1.4 Disability-adjusted life-years (DALYs) attributable to household air pollution. (From WHo global
observatory map. © WHo 2011. All rights reserved.)
 12 What causes disease?

measures, the number of people smoking continues

to increase (Fig 1.7).

ASBESToS-rELATED LuNG DISEASE

Asbestos is a crystalline silicate mineral that has been

Figure 1.5 An axial CT scan showing a soft-
tissue mass arising from the floor of the bladder
(blue arrows). Tobacco smoke is one of the
main culprits in the development of bladder
cancers. Some occupations, such as bus driving
and working with rubber, are also associated
with exposure to toxins, such as benzidine and
2-naphthylamine, implicated in the development
of bladder cancer.
contribute to the production and progression of
atherosclerotic plaques. The estimated number of
smoking-related deaths worldwide is more than 4 mil-
lion and, sadly, despite educational and public health
mined for centuries and used in building insula-
tion because of its advantageous physical properties.
Exposure and inhalation of asbestos fibres lead to a var-
iety of disease processes in the lung, resulting in death
or considerable disability (Fig. 1.8). Asbestos is now
banned in many countries.
We have included drugs in the category of chemical
causes. This is clearly true when thinking about drugs
of abuse (e.g. amphetamines) or deliberate overdoses
of therapeutic drugs. It is rather more complex when
considering the ‘side effects’ of medications. These
are very important because almost all treatments have
some unwanted effects and patients are commonly on
several different types of medication. However, the
detail is beyond the scope of this book and we just
highlight a few exemplars in the relevant chapters
(Fig. 1.9).

Table 1.2 Effects of some tobacco smoke

elements

Component Action
Part 1: Disease, health and medicine

Polycyclic aromatic Carcinogenic

hydrocarbons
Benzopyrene Carcinogenic
Nitrosamine Carcinogenic
Nitrogen oxides Damage cilia and irritate
mucosa
Formaldehyde Damage cilia and irritate
mucosa
Carbon monoxide reduce oxygen delivery to
tissues
Nicotine Stimulate ganglia and Figure 1.6 Coronal CT scan showing a speculated
tumour promotion mass in the right upper lobe – a primary lung
cancer.

Case study: coughing up blood
A 64-year-old woman presents to her GP with a
3-month history of breathlessness and occasional
episodes of haemoptysis. She is known to have
chronic obstructive pulmonary disease but thinks
that her shortness of breath is worse than she
normally expects from her CoPD. She is also very
worried by the haemoptysis.
Her previous medical history includes CoPD and
hypertension. Her hypertension is controlled with an
angiotensin-converting enzyme (ACE) inhibitor. She
smoked 15 cigarettes a day from age 20 to age 60
(when her CoPD was diagnosed).
Examination of the cardiovascular and abdominal
systems is unremarkable. There is a mild reduction
in expansion in the right lower zone; the percussion
note is a little dull and the breath sounds are quiet
relative to elsewhere.
Question: What diagnosis must be considered?
Answer: In a patient of this age, who is a
smoker or ex-smoker, and presents
with haemoptysis, bronchial
carcinoma is a definite possibility.
The GP arranges an urgent referral to the local
chest clinic but receives a request for a home
visit from the patient 4 days later. Her dyspnoea
has worsened and she now has a cough that
is productive of green sputum. She has pain
on inspiration on the right side of her chest.
Examination reveals decreased expansion on the
right side of the chest which is of a greater degree
than 4 days previously. The percussion note is dull
over the right lower zone, again to a greater degree
than when the patient was first examined. The
breath sounds over the right lower zone are quiet
and have the quality of bronchial breathing. The
breath sounds elsewhere in both lungs are normal.
Question: What has happened and how do all
the patient’s symptoms at this stage
relate to her suspected diagnosis?
Answer: The majority of bronchial carcinomas
develop as masses in the proximal
bronchi, near to the hila of the lungs.
As with other tubular structures/organs
in the body, if a tumour develops, from
either the mucosal lining of the tube or
the deeper tissues of the wall, the tube
Chemical causes 13
may become partially or completely
obstructed by the neoplasm.
Narrowing of a bronchus impedes
airflow in and out of the part of the
lung distal to that airway. If the volume
of lung affected is sufficiently great, this
can manifest as dyspnoea, especially in
a patient who has CoPD and therefore
has decreased lung function anyway.
In extreme cases, the obstruction
is complete and causes collapse of
the affected part of the lung. The
findings in this patient on presentation
suggested an element of collapse.
If a region of the lung is obstructed,
the drainage of mucus and other airway
secretions from that lung is impaired.
Stagnant fluid is an advantageous
environment for bacteria and they
can colonise the fluid. In the lung, this
leads to pneumonia in the occluded
region. The immune system reacts with
an acute inflammatory response, lead-
ing to the generation of pus which is
coughed up as purulent sputum.
Extension of the pneumonic
process to the pleura induces
inflammation there. Movement
of an inflamed parietal pleura
over the visceral pleura, as occurs
naturally during respiration,
produces pain.
Haemoptysis may result from two
mechanisms: in addition to its abil-
Chapter 1: What causes disease?
ity to obstruct the lung, a bronchial
carcinoma can ulcerate the mucosa
and will invade deeper structures.
This damage may be accompanied
by small quantities of blood loss. The
other process that generates haemop-
tysis is cavitation. Malignant tumours
are frequently rapidly growing and in
some instances grow faster than their
ability to induce adequate angiogen-
esis. When this happens, part of the
tumour becomes necrotic and may
undergo cavitation. This destructive
collapse can be accompanied by
haemorrhage.
(Continued)
 14 What causes disease?

(Continued)
This is part of Case 6 taken from the book
Pathology in Clinical Practice: 50 Case Studies, which is
complementary to this book as it contains more
advanced clinically relevant information. Have a
look at that so that you can decide if it is useful for
your programme.
Read more in Pathology in Clinical Practice Case 6

Percentage of tobacco use among adults, 2005

s14.6
14.7–22.5
22.6–28.5
28.6–36.5
>36.5
Data not available

Figure 1.7 Percentage of tobacco use among adults. (From WHO global observatory map. © WHO 2008.
All rights reserved.)
Part 1: Disease, health and medicine

Figure 1.9 Amiodarone and the liver: an iatrogenic

Figure 1.8 Axial CT scan showing calcified
pleural plaques (blue arrows) and a fibrotic process
with increased interstitial thickening at the bases
(red arrow). The latter is also known as asbestosis
and is associated with progressive respiratory
dysfunction.
chemical cause of liver disease. Amiodarone is a drug
used in the treatment of cardiac arrhythmias. It can
potentially have side effects on the liver, ranging from
abnormal liver function tests to, rarely, cirrhosis.
Over the long term amiodarone is deposited in the
liver, resulting in a change in the density of the liver
on a CT scan. The normal liver should be the same
density as the spleen (red arrow). However, this
patient’s liver has a higher density (blue arrows) in
keeping with amiodarone accumulation.
 Structural causes 15

Genes are extremely important during normal

STruCTurAL CAuSES
Structural causes include conditions that are con-
genital and produce obvious physical disabil-
ity (Fig. 1.10), such as neural tube defect, or are
acquired, such as acute obstruction or rupture of
blood vessels or parts of the bowel. The cardiovascu-
lar structural conditions are covered in Chapters
7–8 which describe thrombosis, embolism and
atherosclerosis.
The congenital conditions are often of unknown
cause but some have clear genetic or infective causes.
development and mistakes that occur during the produc-
tion of gametes, fertilisation of the ovum and formation
of the embryo can result in malformation or death. A key
concept is ‘body patterning’, which provides a basic ana-
tomical organisation through creating gradients of gene
products. For example, the four HOX gene clusters create
a gradient along the anteroposterior axis of the embryo.
Not all of our organs are paired and symmetrical; as
an example we only have one heart and this should be
situated on the left. To achieve this requires a right–left
differentiation which is dependent on functioning cilia
creating an asymmetrical flow of fluid (Fig. 1.11).

Figure 1.10 (a) Postmortem CT and

(b) MrI on a fetus born with a large
occipital encephalocele – a defect in the
posterior skull bones with herniation
of the brain and meninges through the
defect (yellow arrows). This is one of the
types of neural tube defect. others include
spina bifida and anencephaly.

a b

Chapter 1: What causes disease?

Figure 1.11 Kartagener’s syndrome is due to abnormal

cilia that affect embryonic development – chest
radiograph showing the situs inversus or ‘mirror
imaging’ component of the syndrome, with the apex of
the heart pointing to the right (blue arrow), a
right-sided aortic arch (red arrow) and a gastric air
bubble (yellow arrow) on the right side.
 A systems-biology approach to understanding the ciliopathy diso... https://genomemedicine.biomedcentral.com/articles/10.1186/gm275
Cilia maintain separate cytoplasmic and membrane compartments, but are completely lacking vesicles. Instead cilia rely on specialized modes of transportation called intraflagellar transport (IFT)
to deliver cargo proteins and lipids along the axoneme. IFT can operate in the anterograde direction (towards the ciliary tip) using complex B factors, or in the retrograde direction (towards the
ciliary base) using complex A factors; together these factors regulate the transport speed and net cargo flux. An important, recently emerged aspect of cilia is the gatekeeper role of the septin
family of proteins, regulating initial entry and exit of ciliary factors at the base of the cilium [1]. The transition zone, where the gatekeeper functions, is an adjacent structure at the base of the
cilium, forming the linkers between microtubule and ciliary membrane; it is probably required for unloading ciliary-directed cargo and sorting ciliary-based signaling mechanisms [2] so that the
cell can interpret their context.

Emerging genetics of the ciliopathies

16 What causes disease?
Although ciliopathies are individually rare disorders, an amazing spectrum of what were previously disparate syndromes is now recognized as part of the ciliopathy spectrum. Ciliopathies can be
subdivided into 'motile ciliopathies' and 'non-motile ciliopathies', although we usually define ciliopathies as disorders that result from aplasia and/or disrupted function of primary cilia. Motile
ciliopathies comprise a class of disorders displaying prominent situs inversus (a condition in which the normal positions of organs are reversed). Non-motile ciliopathies show prominent but
mixed features in several vital organs, including the brain, kidney and liver, and others, such as the eye and digit. Ciliopathies range from largely organ-specific disorders, such as polycystic
kidney disease (PKD), to pleiotropic disorders, such as cerebello-oculo-renal syndrome (CORS), Bardet-Biedl syndrome (BBS), Jeune asphyxiating thoracic dystrophy (JATD) and Meckel-
Gruber syndrome (MKS) (Figure 2). All ciliopathies known so far show a recessive mode of inheritance, either autosomal or X-linked, with strong evidence of genetic modifiers that determine
expressivity. Moreover, clinically distinguishable ciliopathies often result from mutations in a single gene (Table 1), suggesting complex genetic networks.

Figure 1.12 Almost every organ

in the body shows vulnerability
in the ciliopathies. Most
ciliopathies have overlapping
clinical features in multiple
organs. Cystic kidney and
retinal defects are frequently
observed. Skeletal dysplasia is
predominantly seen in JATD,
oFD1 and EVC.
ALMS, Alström’s syndrome;
BBS, Bardet–Biedl syndrome;
CorS, cerebro-oculo-renal
syndrome; EVC, Ellis–van
Creveld syndrome; JATD, Jeune
asphyxiating thoracic dystrophy;
JBTS, Joubert’s syndrome; LCA,
Leber’s congenital amaurosis;
MKS, Meckel’s syndrome; NPHP,
nephronophthisis; oFD1, oral–
facial–digital syndrome type 1;
PCD, primary ciliary dyskinesia;
PKD, polycystic kidney disease.
(reproduced from Lee and
Gleeson. Genomic Medicine
Figure 2 2011;3:59.)
Almost every organ in the body shows vulnerability in the ciliopathies. Most ciliopathies have overlapping clinical features in multiple organs. Cystic kidney and retinal defects
are frequently observed. Skeletal dysplasia is predominantly seen in JATD, OFD1 and EVC. ALMS, Alström syndrome; BBS, Bardet-Biedl syndrome; CORS, cerebello-oculo-renal
syndrome; EVC, Ellis-van Creveld syndrome; JATD, Jeune asphyxiating thoracic dystrophy; JBTS, Joubert syndrome; LCA, Leber congenital amaurosis; MKS, Meckel syndrome;

Just to give you an idea of the complexity, Fig. 1.12

NPHP, nephronophthisis; OFD1, oral-facial-digital syndrome type 1; PCD, primary ciliary dyskinesia; PKD, polycystic kidney disease.

Table 1
respiratory tract (and other) cancers and cardio-
is a picture of some congenital abnormalities associ-
Ciliopathies, genes and subcellular functions of the proteins vascular disease.
ated with ciliopathies and the genes involved. Please What makes troubling reading is the fact that, in
3 of 10 22/04/2016, 10:18
don’t attempt to memorise these; just be grateful low- and middle-wealth countries, the average age
that you can look them up on genetic databases when at which deaths occurred is considerably lower than
required. in the wealthy countries. Of deaths in affluent coun-
tries 87% are from CVDs and cancers, compared with
Part 1: Disease, health and medicine

37% in low-income countries. Deaths due to infect-

ive causes and poor hygiene are far more common in
WHICH ArE THE MoST IMPorTANT low- and mid-income countries, of which tuberculosis,
DISEASES ToDAY? diarrhoeal diseases, malaria and HIV/AIDS are major
contributors. Tuberculosis (TB) is second only to HIV/
The World Health Organization (WHO) 2012 mor- AIDS as the greatest killer worldwide due to a single
tality statistics show that, of the 56 million people infectious agent and TB causes a quarter of all deaths in
who died in 2012, ‘non-communicable diseases’ HIV/AIDS patients.
caused 68% of all deaths: cardiovascular diseases
(CVDs – mainly ischaemic heart disease and strokes),
cancers, diabetes and chronic lung diseases were BIoLoGICAL AGENTS AS CAuSES oF
the most important of these. ‘Communicable’, i.e. DISEASES
‘infectious’, maternal, neonatal and nutritional con-
ditions together caused 23% of global deaths, and Infectious causes are especially important because
injuries caused 9%. The use of tobacco is thought of the number of people affected worldwide and the
to be at the root of 10% of all deaths, largely from fact that many are treatable with antimicrobials.
 Biological agents as causes of diseases 17

read more about bacterial infection in changes in the classification of some medically
Pathology in Clinical Practice Case 7 important microbes.

Bacteria are generally classified according to their TAXoNoMY

shape and whether they stain blue–purple with the
Gram stain (Fig. 1.13 and Table 1.3). Endotoxins
and exotoxins are important mechanisms by which
they cause damage and these are described in detail in
Chapter 2 page 72.
Advances in molecular biological techniques
have led to some significant changes in medical
microbiology. Most importantly there have been
Membrane
DNA in protein
nucleus
Microbes were traditionally classified on the basis of
their microscopical morphology, culture requirements,
biochemical and serological properties – in other words
their phenotypic characteristics. Nucleic acid amplifica-
tion and genome sequencing mean that organisms can
now be speciated by their genotypic properties. In bac-
teriology this has resulted in the reclassification of many

The peptidoglycan wall contains techoic

acid and can stimulate an acute
inflammatory response
Organelles

Gram-positive bacteria stain blue with crystal violet, which lodges in their thick outer
wall. Inside they have a double-layered phospholipid membrane, with membrane
proteins, surrounding cytoplasm with organelles and a circular nucleus composed of
double-stranded DNA

LPS Outer coat contains lipopolysaccharide (LPS),

a component of which causes endotoxic shock,
fever and diarrhoea. Porin protein allows nutrient
transfer
Periplasmic space contains enzymes and
proteins in a gel
LPS
Thin peptidoglycan coat

Gram-negative bacteria have an extra, double-layered coat that traps crystal violet before
it can reach the peptidoglycan coat (which is thinner than in G+ bacteria).The violet crystals
are washed out by alcohol as part of the Gram staining process and the bacterium is visualized
using a red counter-stain

Bacterial shapes

Chapter 1: What causes disease?

Cocci Other
Staphylococci

Diplococci Corkscrew

Coccus
Vibrio

Streptococci
Filamentous
Bacilli Spirochaete
Helical form
Coccobacillus Bacillus

Bacterial shapes – bacteria are classified by their shape and groupings as well
as their Gram staining. Bacteria can be circular, rod shaped, spiral, curved and/or have flagellae.
They can occur singly, in pairs (diplo), clusters (staphlo) and strings (strepto); eg streptococci.

Figure 1.13 Gram-negative and Gram-positive bacteria.

 18 What causes disease?
Table 1.3 Simple summary of the ways to classify bacteria
Gram-positive
Examples of aerobic and anaerobic bacteria
obligate aerobes Bacillus cereus
Facultative anaerobes Bacillus anthracis
Staphylococci
Microaerophilic bacteria Streptococci
obligate anaerobes Clostridia
Examples of morphologically distinct Gram-positive and Gram-negative bacteria
Cocci (spherical) Streptococci (in chains).
Staphylococci (in clusters)
Bacilli (rod shaped) Corynebacteria
Clostridia
Bacilli
Listeria spp.
Spiral
Pleomorphic
Branching Actinomyces, Nocardia spp.
medically important organisms and, in some cases, this
confusingly means that the name of the organism has
changed, often with the generation of a new genus to
comply with taxonomic rules. A good example is in
Part 1: Disease, health and medicine
the genus Pseudomonas where the organism Pseudomonas
maltophilia (a cause of bacteraemia in immunocom-
promised patients) became Xanthomas maltophilia, and
is currently known as Stenotrophomonas maltophilia and
where the organism Pseudomonas cepacia (a cause of res-
piratory tract infection in patients with cystic fibrosis)
is now Burkholderia cepacia. Some organisms have now
been found to be made up of a complex of several dif-
ferent species. The genus Streptococcus is a good example
of this: Streptococcus bovis has now been divided into two
species – Streptococcus gallolyticus and Streptococcus pasteur-
ianus. Is this important? In some cases it has little prac-
tical relevance, but in the case of the former Streptococcus
bovis it does. It was known in the past that there was
an association with colonic carcinoma in patients who
Gram-negative Acid fast
Neisseria spp. Mycobacteria
Escherichia coli
Salmonellae
Spirochaetes
Bacteroides spp.
Neisseria spp.
Haemophilus spp.
Bordetella spp.
Klebsiella, Proteus and Shigella spp., E. coli
Vibrio, Salmonella spp.
Treponema, Borrelia, Leptospira
(spirochaetes)spp.
Helicobacter, Campylobacter spp.
Rickettsia spp. (intracellular obligates)
had a bacteraemia with this organism. It has now been
shown that this association is really with Streptococcus
gallolyticus not with Streptococcus pasteurianus. More pro-
foundly, some microbes have been found to have been
completely misclassified. Pneumocystis carinii, which can
cause respiratory infection in immunocompromised
hosts, is no longer classified as a protozoan and is now
known to be a fungus and has been renamed Pneumocystis
jirovecii. Molecular techniques such as 16-S ribosomal
DNA polymerase chain reaction (PCR) have allowed
previously unculturable organisms to be identified,
e.g. the bacterium Tropheryma whipplei, the cause of
Whipple’s disease.
Although most infectious disease is due to bacteria
and viruses, there are other categories that are just as
important, and that have evolved their own mechanisms
for bypassing host defences and causing disease. Briefly,
these are the fungi, protozoa, parasites, helminths and
prion proteins.
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of Children of men
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.

Title: Children of men

Author: Eden Phillpotts

Release date: October 23, 2023 [eBook #71941]

Language: English

Original publication: London: William Heinemann Ltd, 1923

Credits: Al Haines

*** START OF THE PROJECT GUTENBERG EBOOK CHILDREN

OF MEN ***
 CHILDREN OF MEN

BY

EDEN PHILLPOTTS
AUTHOR OF "EUDOCIA," "BRUNEL'S TOWER," ETC.

LONDON
WILLIAM HEINEMANN LTD.

First Published, 1923

PRINTED IN GREAT BRITAIN BY WOODS & SONS, LTD., LONDON W.1.

FOREWORD
 The egotism of a personal note may, for once, be permitted to me, since
an enterprise, launched some thirty years ago in 'Children of the Mist,' now
reaches its port of destination with the present story. When 'Widecombe
Fair' was written, that book appeared the end of the matter; but fresh
challenges from life on the Dartmoors, and renewed strength to meet them,
enabled me to add certain passages to the total and render the design
orbicular and complete. With 'Children of Men' it is accomplished and the
purpose may be related in brief words.

Without learning, or bias, or convictions to determine my trend, I have

said 'Yes' to life as it unfolded in this small theatre. Mine was neither a great
nor a subtle vision, but unvitiated within its limitations.

Given faith that conscious Will is at the helm of human affairs, then a
definite attitude must result before the spectacle of humanity; but if the
mind be built to accept only unconscious Law as controller, the outlook
differs and a resolute trust may develop in man, as ultimate arbiter of his
own destiny. Neither assumption can be proved, or disproved; but the
relation of a controlling, guiding Spirit to the Universe lies open to doubt;
its subjection to Law does not; and building upon this latter certainty, I
discovered, in the evolution of the moral principle, full cause for trust and
for hope.

Observation has convinced me that moral evolution is upward, despite

massive, contemporary evidence to the contrary. For the War and the peace
alike I recognise as a transient paralysis of human reason, not its negation.
The War was an attack of familiar maladies for which man's own errors of
ignorance were to be condemned, not the laws of his being; but it was an
unutterable infamy and disgrace to him, for this reason, that it proves him to
be lagging behind the time-table of moral evolution. Ere now he should
have outgrown his present stature, and the causes of his tardy progress, his
centuries of loitering in the desert, are as plain as pitiful. An impartial ethics
can point to where his faith took the wrong turn; but progress in
righteousness is only delayed; I have seen dawn upon the mountain tops too
often not to trust that it will presently descend into the shadowed homes and
sleeping hearts of men.
 Fortified by this opinion—the only opinion I ever clung to—my instinct
turned from the way of least resistance on easy and level lands and strove to
climb, to sacrifice without regret the highest, best, most hopeful, as life
itself actually does. Thus only is the vitality of the creator proved in his
creation and tragedy achieved, which, according to the measure of an artist's
endowment, is clean, cathartic, inspiring and obedient to the laws and
realities of things as they are. Irrationalism chokes under this atmosphere:
only the humanist can breathe it.

But the world grows braver, for we have seen great artists open its eyes
and blow the breath of honesty and truth into its lungs; we have seen the
sentimental vapours of the past dispelled in the freedom that art now
attains; we have seen the artist pitiless, that his audience may learn the
meaning of pity; ugly, that others may find wherein true beauty lies.

By the kindness of Messrs. Heinemann and The Macmillan Company

full titles of my Dartmoor cycle are recorded on another page; and it is a
source of deepest gratification to know that in the future, when conditions
of production admit it, they design for me a definitive edition. His
publishers can pay no author a greater compliment than that, and I take this
opportunity to thank them for the highest distinction my work has ever
brought.

As a man's footsteps in the dew of the morning are the labours of the
minor artist; but if he challenge surer feet and greater strength to pursue his
quest before the dews are dried and his passing forgotten, then he also has
played a part. The masters flash lightning through our clouds of human
passion, ignorance and error, or hang rainbows of promise upon their
gloom; but for us of the rank and file, it is enough that we make happy such
as have only heard of happiness and waken the dayspring of courage in
fearful hearts; it is enough if we kindle one valley mist with a gleam of
beauty, or pour some few, pure drops of hope into the thirsty and percipient
soul.

E. P.
 CONTENTS

PROLOGUE

CHAPTER

I. Betrothal
II. On Ugborough Beacon
III. The Rescue

BOOK I

I. Jeremy
II. At Red House
III. Barton Gill Under Notice
IV. On Shipley Bridge
V. The Children
VI. Huntingdon Warren
VII. Sunday
VIII. The Revel
IX. The Gift
X. After the Holiday
XI. The Offer of Owley
XII. On the Hill
XIII. The Oranges
XIV. End of a Home

BOOK II.

I. Chorus
II. Verdict
III. Utility
IV. Auna Tries
V. Revenge
VI. The Witch Doctor
VII. At Jacob's Bedside
VIII. Jeremy Evasive
IX. Jacob Comes Home
X. Flight
XI. After the Wedding
XII. A Problem for Auna
XIII. At the Barbican

BOOK III.

I. 'Mother's Stone'
II. Driving in the Ponies
III. The Pilgrim Fathers
IV. Evening Star
V. The Autumn Wind
VI. The Children
VII. William's Birthday
VIII. Jeremy
IX. Exodus
X. Fever
XI. Jacob Lives
XII. The Christening
XIII. The Promise

CHILDREN OF MEN
 CHAPTER I

BETROTHAL

On a day in high summer the valley was full of light, and Auna River,
her moorland journey ended, bowed under a plantation of pine and fir, then
sparkled forth, to learn what welcome awaited her in the lower lands.
Above the stream, easterly, a green hill towered against the sky; stunted
thorns broke the sweep of the eagle fern, grey rock clitters spread and cloud
shadows drifted over all, to cool the brightness.

A wood massed beneath in the mouth of the vale, and from this dusky
retreat there leapt the river, in a succession of planes broken at each little
fall by an apron of granite. Here the ripples flashed with foam; here the blue
of the sky was caught in the gliding surface between, where Auna's tresses
twined soberly, and fern, heather, woodrush cast their reflections into her
tremorous mirror.

Two stone shelves presently barred the waterway and, leaping one, the
river made a circular sweep above the second and eddied in a little
backwater. The later ledge was gentle and its steps sloped to three feet
above the stream. It was fringed with herbage and flowers, and here Auna
loitered, making shadows for fingerling trout to play in. Through the limpid
crystal there shone agate and amber tones of rock and pebble beneath; and
these warm colours were repeated in the tunic, breeches and gaiters of a girl
who sat above the pool.

Round her thronged a dozen lesser lives, that wove a restless, ruddy
pattern about her feet, in her lap and upon her shoulders. Girl and puppies
completed the harmony and made a splash of rich, auburn light beside the
river. The Irish terriers kept on the move about their kennel-maid and
seemed to flow over her, as the stream flowed over the stones. They nuzzled
her cheeks, licked her fingers, thrust their noses into the black hair coiled up
under her cap. She was a slim, brown girl with grey eyes, that seemed large
for her small features, and a pretty, yielding mouth. She was tall and of
maidenly slimness; her little breasts moved under the light garments that
she wore; she laughed and played with the puppies; but a deeper joy than
they could give lighted her face.

"Leave me alone, my chicks!" she said, and pushed them away from her
with both hands. They scattered, tugging and tumbling; then, while the girl
tidied her hair and stilled her laughter, the puppies set up their infant
barking; and she knew that somebody must be upon the by-road that ran
parallel with the stream.

She rose, jumped over the narrow neck of the pool and joined the man
who was coming up the valley. The puppies already swarmed round his
heels.

"Could you get it?" she asked, and the man held up a large tin.

"Just in time," he answered. "They were starting off with the cream to
Brent, but Mr. Winter spared me a pound."

"Are they settling in pretty clever?"

"Yes; they're getting straight."

Jacob Bullstone stood half a foot taller than the girl and was fifteen
years older. Now a great thing had happened to him, and, at thirty-five, one
whom his neighbours declared would remain a bachelor was in love with
his kennel-maid and engaged to be married. He owned varied possessions
and, thanks to an industrious and prosperous father, inherited some fortune.
Two farms were his property in the lap of Ugborough Beacon, at the
foothills of the moor a few miles from his home; while here, beside the
river behind the pine wood, he dwelt with his widowed mother and pursued
the business dearest to his own heart.
 Bullstone bred a famous strain of red Irish terriers and sustained the
reputation that his father had won before him. He was a man of good
education, great energy and high principle, and he lived a narrow life. He
had never roamed, but found his intelligence and spirit of enquiry satisfied
in his native environment of moor and vale, comfortable state and
interesting occupation. He did not guess that his outlook was limited, for he
had been educated at a grammar school and thought himself to possess
clearer wits than most of his neighbours. The fact, together with his
prosperity, made him satisfied with his own accomplishments and wits. His
old mother did nothing to modify his self-judgment; but none ever found
the man unfriendly or puffed up, for he was of a kindly, generous
disposition, did good things and held it no fault in another to differ from his
opinions.

Love, however, opened Jacob's mind to a lack in himself that he had not
suspected. He still felt timid and distrustful before the depths of ignorance
revealed by his new emotions.

In person Jacob Bullstone was large and heavily modelled, with broad
shoulders and a clean-cut, swarthy face. His eyes were dark brown and of a
sulky cast in repose, but the expression belied him. He had a low, wide
forehead, a square jaw and heavy chin. He shaved clean and his mouth was
large and well shaped. He kept his black hair so short that the lines of his
skull were clearly seen. It sloped rather steeply backward from the brow
and bulged a little above his small ears.

He was hatless and clad in tawny tweeds with black leggings and a
dirty, red waistcoat. He walked with a long stride, that he was now taming
to go with Margery Huxam's footsteps, and for adornment he wore his
father's gold signet-ring on the little finger of his left hand and the silver
mask of a fox in his green tie.

The lovers proceeded together deep in their own concerns, for they had
been betrothed a week; the startling news was known at Margery's home in
Brent, four miles away down the valley, and to-day her parents and her
brother were coming to the kennels, that they might dine with Mr. Bullstone
and his mother.
 The cream from Shipley Farm was for them.

Margery Huxam had turned kennel-maid for love of the life and not
because any reason existed that she should earn her own living. Barlow
Huxam, her father, kept the post-office at Brent as an addition to his own
prosperous drapery establishment. He had but two children living, and
Margery, who adored dogs and understood them, came to Red House, Jacob
Bullstone's home, that she might fill the vacancy until he should be suited
with a new assistant.

The families were long acquainted and Mr. Huxam, little dreaming that
such a great matter would spring from the incident, raised no objection to
his daughter's wish.

She came for a fortnight in friendship, but liked the work so well that
she presently proposed to stop on at a salary; and since she had proved
herself skilled and had won the affection of old Mrs. Bullstone and Jacob's
head kennel-man, he was glad to secure her.

Her parents, however, protested and, after six months, began to agitate
for the return of their only daughter; but when Judith Huxam demanded that
Margery should come home again, the dog-breeder had discovered that his
future happiness depended upon her.

Their courting, at first almost unconscious, proceeded quickly towards

the finish, for man and woman were of a mind, and though a gap of fifteen
years separated them and made Bullstone fearful when he found the truth,
circumstances combined to diminish this disparity, for the girl had been
bred in a puritanical home under a strenuous mother, who regarded
happiness at best as doubtful. Margery's experience of young men was
exceedingly limited and, to her, Jacob's sobriety, steadfast outlook and fixed
opinions were more attractive than the happy-go-lucky attitude of her own
generation. She loved him very heartily before he had given a gleam that he
also was in love; but her emotion had been of a gentle pattern and thrust
away with secret blushes as something near akin to wickedness. She felt a
gulf was fixed between such an important, well-to-do man and her young
self. Indeed she did not even suffer, but rather laughed at herself for her
moonshiney dreams. Then came the evidence from the other side and she
was overwhelmed to find her power over one regarded as unyielding before
women. He approached her with humility, declared genuine pride and
satisfaction on the discovery of her love, rejoiced to learn that he seemed
not too old to her and instantly acquainted her parents with the fact that she
had consented to wed him.

Barlow Huxam declared gratification, but his wife was not so well
pleased.

The match, while in every respect a brilliant one and beyond what they
might have hoped for Margery, found her mother in some doubt. She
suspected that fifteen years was too great a difference of age; and she
professed uncertainty concerning the past life of a bachelor of thirty-five.
She did not know anything against Bullstone, or his parents before him; she
could not name the quality of her suspicions, yet she questioned Margery
very closely and warned her of the step that she designed. But no permanent
cloud appeared and Jacob conducted himself in a manner to disarm Mrs.
Huxam; for his views of matrimony satisfied her and he proposed a
settlement that could only be regarded as generous. In this matter, however,
Barlow Huxam was not behind his future son-in-law.

Twice on Sundays the lover brought Margery to her family, and twice he
worshipped with them at their tabernacle. His behaviour was agreeable to
Mrs. Huxam and her doubts finally dwindled.

To-day, while Margery and Jacob walked side by side towards Red
House, nestling under a shoulder of the hill behind the pine woods, the girl's
parents and her brother were already upon their way, tramping through
shady lanes upward through the valley to Shipley Bridge.

"I'd best change into a petticoat before they come," said Margery.
"Mother little likes my breeches, and thanks God I shan't wear 'em much
longer."

"I feel the same," said the man. "You know I'm at you to doff them once
for all."
 "I love 'em," she declared. "I'll miss them cruel. You courted me while I
was in 'em, and I shall put them on now and again—for luck. Petticoats
slow your going and be tame after breeches."

"'T was never heard that man and wife both wore 'em," he said.

They passed through the woods with the puppies galloping round about,
and then they came to the stone-built home of the Bullstones—a granite
house under red tiles, which covered the upper storey of the walls also. It
basked under the hot sun in a hollow notch of Black Tor, while the river ran
at its feet and a grass lawn spread before the windows. Above, on the
hillside, were scooped terraces where grew cabbage and turnip, and beyond
sprang the trees to the hill crest westerly. Laurel and rhododendron made
the slope snug; the kennels extended behind the house, while Bullstone's
property spread to the other side of the river also and there an acre or two
had been cleared, where potatoes grew in the rich alluvial. Fowls and ducks
flourished at stream side and the link between Red House and the outlying
cultivation was a bridge of pine logs thrown across Auna, where her banks
rose high.

Everything about the place was neat, trim and stern. The hedges were
clipt, the ground clean; for Jacob Bullstone's mother was an old-fashioned
woman and had lived with a husband inspired by the same ideas.

"The highest beauty be tidiness," Mrs. Bullstone never wearied of

declaring, and her son was content to echo that opinion. His home and its
surroundings proclaimed the distinction of use, but none other. There were
no flower beds, no attempt to decorate house, garden, or river. Indeed Auna
was chastened by stone-built banks, until she passed southerly away to the
rocks and rapids and the deep mossy pools, where Red House ducks and
geese spent their pleasantest hours. Nature strove with man, but man
conquered for a little space.

Mrs. Bullstone was at the door and repeated her son's directions, as she
took the cream from him.

"Get up to your chamber and doff them clothes, Margery. I well know
your mother don't hold with 'em and I hope you won't wear 'em no more."
 "I'm kennel-maid a little longer, mother," replied the girl. Then she
entered and Jacob conducted the puppies to their quarters. Behind the house
was a large exercise yard, with open compartments wired off round about it,
a boiler house for the preparation of food, and various buildings on two
sides of the square. The red mothers of the puppies welcomed them back
and the little things knew their parents. Separated dogs barked to Jacob
from enclosures and pressed their noses through the bars; but all were of the
same breed and to an untrained eye exactly resembled each other. Jacob
accosted a few, then turned to a man who was mixing food.

"The goats are gone up Shipley Tor," he said. For goats were a feature
of the establishment. A little flock was kept, since goats' milk in Bullstone's
opinion was the primest food for new born dogs.

Barton Gill, though bald and wrinkled, was not so old as he looked. As
a lad he had worked for Jacob's father and was now little more than fifty,
though he appeared to be nearer seventy. He was slow of voice and gesture,
but still was strong and hearty behind his wrinkles and somewhat
pessimistic view of life.

"They goats be the bane of my days," he said, "and a time's coming

when I shan't be able to keep pace with the toads."

Jacob laughed shortly.

"Must be grizzling—and you only in your full manhood, as we all

know."

A mile away walked slowly Barlow Huxam and his wife, while Jeremy,
their son, a lad of fifteen, loitered behind them, to play and fling stones; but
he kept his parents in sight. Mr. Huxam, a solid fair man of five and forty,
mopped his brow and declared that he must rest and grow cooler before
proceeding.

"We ought to have hired Mr. Catt's little chaise as I ordained to do," he
said. "'Tis drouthy weather and a thunder-storm promising for certain."
 His wife, however, did not agree with him.

"You don't take enough foot exercise, Barlow. If you was to walk more,
it wouldn't pour out of you same as it does. There's no thunder in the air,
else my head would know it. We'll rest by the bridge since we're a thought
before time."

Judith Huxam—a daughter of the prosperous race of the Pulleyblanks

—-was the same age as her husband. A dark-haired, neat woman was she,
who put folk in mind of a bantam hen. Always trim, alert and self-
possessed, character marked her face, voice and opinions. She was pious,
with the piety of a generation now vanishing away, and also very proud; but
she had the instinct to hide much of herself from the world, being seldom in
her neighbour's houses and restrained in the matter of criticism. She was
stern and never forgot a wrong; but she accepted everything that happened,
because she held it her duty to do so. She ruled her husband and her
children as a matter of course, and Mr. Huxam pretended greater
enthusiasm for her bleak religion and opinions than he felt; but he
entertained the keenest admiration for her and, if he ever differed from her
conclusions, it was only in his mind. He never crossed Judith, but supported
her rule in the home, as he had long since fallen in with her conduct of the
shop. Her face was strong and her natural expression attractive, for she had
a frank gaze and regular features. But her grey eyes were hard, and while a
pleasant, receptive expression marked her features, her lips were set closely
together. She never laughed and rarely smiled, save conventionally upon
customers. She dressed in puritanical fashion and eschewed finery. Her dark
brown hair was parted in the middle and curled up closely behind in a plain
roll. She wore a small bonnet and always dressed in grey. Her voice was
rather low pitched and of agreeable quality, but she spoke little save to the
purpose. Indeed she distrusted volubility.

The drapery establishment reflected Judith, and young people rarely

patronised it save for necessities. The maidens of Brent held that if you
wanted clothes that wouldn't show, Huxam's might be sought; but for
adornments, fripperies and "fal-lals," one must seek elsewhere.

At Shipley Bridge the road crossed the river half a mile below Red
House; and here Mr. Huxam stopped, where, shaded by oak trees, there
spread inviting herbage.

"We'll sit here on the spine grass for ten minutes while I cool down," he
said.

He subsided, opened his waistcoat and dabbed his face, hands and neck
with a white handkerchief, while Mrs. Huxam called her son, tidied him,
made him dust his boots with a frond of fern and walk beside her for the
rest of the way.

She looked at a gold watch on a thin gold chain, then paced to a gate a
few yards distant and regarded the roof of a farm that rose under the flank
of Shipley Tor.

"I wonder how Miss Winter and Adam and Samuel are settling in," she
said. "A bit lonesome after Five Elms, and a poor place, so the last man
always declared."

"The last man would have made a poor place of any place," answered
her husband. "He was always clever at picking the eyes out of a farm and
then leaving it for a better than himself to build up again. And so it will be
here; but Winter's got it at a very low rent, and he's a worker and may do
well. His zany brother's a mighty worker also. The Lord denied wits, but
gave him a strong body."

Mrs. Huxam continued to regard the roof of Shipley Farm without

speaking.

"He's a man who'll come to Sunday meeting no matter how long the
way," declared Barlow Huxam hopefully.

"And his sister too. One of the Chosen her, if ever a woman was chose,"
answered his wife.

Then Jeremy raised a shout and ran over the bridge.

"Here's Margery!" he cried.

 The kennel-maid had put on a blue skirt, a straw hat with a white ribbon
and a plain white blouse. Mr. Huxam rose, while his daughter, having
kissed her brother, now greeted her parents.

"You're hot, you dear," she said to Mr. Huxam; but he declared that he
was now cool again.

They set out, Margery walking between her mother and father, Jeremy
playing with an adult terrier who had accompanied her.

"I hope," said Mrs. Huxam, "that they've made no great meal on our
account."

"They have then. We've got a sucking-pig!"

"A waste, and it ain't the weather for it anyway," declared Judith.

"It's always the weather for sucking-pig," said Mr. Huxam, "though
seldom enough nowadays do any man let himself go in that direction. A
dish for kings, and of such a tender substance that I've never known the day
was too hot to enjoy it. But it asks for mastery in the kitchen. If I'd known,
I'd have let Mrs. Bullstone have a recipe from my old mother's cookery
book. Full of vanished wisdom that book."

"Fuller of vanished greediness," asserted his wife. "People thought more

of their stomachs in them days; at least you Huxam people did. The
Pulleyblanks——"

She stopped and called to Jeremy.

"Don't run no more—quiet down and walk along with me, boy."

Her eyes softened when they rested on her son.

A cool and refreshing shadow embraced them as they entered the pine
wood; then their destination glinted red through the tree stems and Jacob
Bullstone appeared to welcome them.

"Punctual to the stroke," he said.

 "Them as keep a post-office don't fail there," declared Mr. Huxam.
"And how's yourself, Jacob? Still of a mind?"

"So much of a mind that I don't want you people to be gone till
Margery's named the day," answered the lover.

"Plenty of time for that," replied Margery's mother. "There's a lot to be

thought upon."

Her eyes were everywhere. She had a trick to bend her head a little
when she was observing, and now, herself unmarked, Judith took in a
thousand incidents, regarded with approval the spotless purity of the place,
its thrifty details of contrivance and the somewhat brusque and stark lines
of the outlying ground and little grass-covered garden patch.

She had never been here before, but Red House was familiar to her
husband.

Mrs. Bullstone appeared at the door and in five minutes the party sat at
dinner. The parlour was a plain room with a solid table, solid chairs and a
solid and enormous sideboard bright with cups and trophies won by
Bullstone terriers. A few dog portraits hung upon the walls, and the empty
grate was heaped with red pine cones. Jacob sat at the head of the table and
his mother at the foot, while Margery and her father were on Bullstone's
left, Mrs. Huxam and Jeremy upon the right.

The master devoted himself to his future mother-in-law.

"Margery favours you, ma'am," he said, "and Master Jeremy's like his
father."

Judith considered the suggestion.

"I wouldn't say that altogether," she answered. "My children's more
Huxam than Pulleyblank; but Thomas, my eldest boy—who died so brave
doing his duty two years ago—he was very like me."